Why modeling? Mathematical models of the human sleep/wake cycle gives new insights on the pathophysiology of fatal familial insomnia (FFI)

FFI, a rare prion disease, constitutes by their wake and sleep abnormalities a unique pathophysiological model of disease. Recently, a neurobiological-mathematical model of the human sleep/ wake cycle (MMSWC) developed by Rempe, BestJ and Terman, reconciles circadian/homeostatic influences with new findings like the proposed sleep/wake flip-flop switch and REM-NoREM switch. We attempt now to modeling sleep abnormalities seen in FFI patients with the hypothesis that different degrees of perturbation (activation/deactivation) of circadian and homeostatic drives are related with sleep findings previously reported. We modeling our sleep data using MMSWC, where, briefly, the ventrolateral preoptic neurons (VLPO) and monoaminergic neurons (AMIN) inhibit each other and are modeled as a system of two ordinary differential equations. A similar interaction between REM-on and REM-off was also implemented. Both models were able to produce simulations that we confront with reanalyzed polysomnograms of a proven and peculiar case of FFI. IntraREM sleep fragmentation, the cyclic alternating pattern reported in atypical REM sleep and the reversal of atypical REM-NoREM presentation, seen in our case of FFI, can be simulated according the MMSWC by increasing random and Poisson perturbations on circadian and/or REM-on inputs. This was made by modifying the term I AMIN that corresponds to REM-on equations of this model. These mathematical models support the hypothesis that in FFI the extended neuronal network that regulates sleep and wakefulness could be disrupt by altered circadian/homeostatic and REM inputs.